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WO2021084725A1 - Dispositif de détection, composition magnétique et système de gestion - Google Patents

Dispositif de détection, composition magnétique et système de gestion Download PDF

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Publication number
WO2021084725A1
WO2021084725A1 PCT/JP2019/042954 JP2019042954W WO2021084725A1 WO 2021084725 A1 WO2021084725 A1 WO 2021084725A1 JP 2019042954 W JP2019042954 W JP 2019042954W WO 2021084725 A1 WO2021084725 A1 WO 2021084725A1
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WO
WIPO (PCT)
Prior art keywords
magnetic
composition
detection device
field vector
magnetic composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2019/042954
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English (en)
Japanese (ja)
Inventor
宮崎　秀樹
進輔 加藤
泰弘 財満
敬三 中本
哲史 戸谷塚
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eisai R&D Management Co Ltd
Fujidenolo Co Ltd
Original Assignee
Eisai R&D Management Co Ltd
Fujidenolo Co Ltd
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Publication date
Application filed by Eisai R&D Management Co Ltd, Fujidenolo Co Ltd filed Critical Eisai R&D Management Co Ltd
Priority to PCT/JP2019/042954 priority Critical patent/WO2021084725A1/fr
Priority to JP2020181120A priority patent/JP7593614B2/ja
Publication of WO2021084725A1 publication Critical patent/WO2021084725A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/06—Devices, other than using radiation, for detecting or locating foreign bodies ; Determining position of diagnostic devices within or on the body of the patient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/07—Endoradiosondes

Definitions

  • the present invention relates to a detection device for detecting an orally administered magnetic composition, a magnetic composition detected by the detection device, and a management system.
  • a detection system for detecting magnetic substances in the human body has been proposed.
  • the detection system described in Patent Document 1 has at least two sensor components. Each sensor configuration has 1 to 3 anisotropic magnetoresistive sensors.
  • a magnetic field vector based on an orally administered magnetic material is measured in each sensor component.
  • the difference (referred to as vector difference) of the magnetic field vectors measured in each sensor configuration is calculated.
  • the detection system detects the magnetic material based on the calculated vector difference. As a result, the detection system detects swallowing of the magnetic material, passage of the magnetic material through the esophagus, movement of the magnetic material due to peristalsis during digestion, and the like.
  • An object of the present invention is to provide a detection device, a magnetic composition, and a management system capable of detecting an orally administered magnetic substance and capable of miniaturization and cost reduction.
  • the detection device is a detection device that is orally administered into the human body to detect a magnetic composition containing a magnetic substance, and a magnetic sensor having directional anisotropy is placed in at least three different directions. At least one three-dimensional magnetic sensor for arranging and measuring the magnetic field vector formed by the magnetic material contained in the magnetic composition, and an acquisition means for acquiring the time change of the magnetic field vector measured by the three-dimensional magnetic sensor. And the detection means for detecting the magnetic composition in the human body based on the time change of the magnetic field vector acquired by the acquisition means.
  • the detection device detects the magnetic composition orally administered into the human body based on the time change of the magnetic field vector measured by the three-dimensional magnetic sensor. That is, the detection device can detect the magnetic composition using one three-dimensional magnetic sensor. Therefore, the detection device can be miniaturized and reduced in cost.
  • the acquisition means acquires the time change of the angle of the magnetic field vector
  • the detection means obtains the time change of the angle of the magnetic field vector acquired by the acquisition means or the time change of the angle.
  • the detection device can detect the magnetic composition when the angle of the magnetic field vector changes with time, for example, in response to the movement of the magnetic composition in the human body.
  • a plurality of the three-dimensional magnetic sensors mounted at different positions on the human body are provided, and the detection means is a magnetic field vector acquired by the acquisition means among the plurality of the three-dimensional magnetic sensors.
  • the magnetic composition is within the detection range of the three-dimensional magnetic sensor whose value obtained by dividing the time change of the angle or the time change of the angle by the magnitude of the time change of the magnetic field vector is larger than the predetermined amount. It may be detected. In this case, the detection device can accurately detect the magnetic composition from a wide range of the human body.
  • the accelerometer and the determination means for determining whether the state of the position fluctuation of the human body satisfies a predetermined condition based on the output result of the acceleration sensor are provided, and the acquisition means is said by the determination means.
  • the time change of the magnetic field vector may be acquired.
  • the detection device acquires the time change of the magnetic field vector when the human body is in a calm state based on the output result of the acceleration sensor, and identifies the magnetic composition. In this case, since the influence of the position fluctuation of the human body on the measurement result can be suppressed, the detection device can accurately detect the magnetic composition in the human body.
  • the magnetic composition according to the second aspect of the present invention is a magnetic composition detected by the detection device according to the first aspect, which is orally administered into the human body and contains at least a magnetic substance.
  • the magnetic composition can exert the same effect as in the first aspect.
  • a magnetic composition it can be easily administered to the human body.
  • it can be detected more accurately than when it is administered in a magnetic state.
  • the magnetic composition may stay in the stomach for at least 1 hour after being orally administered.
  • the detection device only needs to measure the magnetic field vector intermittently with a three-dimensional magnetic sensor during the period when the magnetic composition is retained in the stomach, and the processing load on the detection device can be reduced, so that the power saving of the detection device can be reduced. It will be possible.
  • the magnetic material may contain iron oxide.
  • the detection device can accurately measure the magnetic field vector by the three-dimensional magnetic sensor.
  • the magnetic material may contain at least one of maghemite, magnetite, and epsilon iron oxide.
  • maghemite magnetite
  • epsilon iron oxide the measurement of the magnetic field vector by the three-dimensional magnetic sensor can be performed more accurately in the detection device.
  • the magnetic composition may further contain an enteric substance.
  • the magnetic composition can be prepared so that the behavior of the magnetic composition in the intestine is as desired.
  • the magnetic composition may further contain a poorly water-soluble substance.
  • the magnetic composition can be prepared so that the behavior of the magnetic composition in the intestine is as desired.
  • the magnetic composition may further contain fats and oils.
  • the magnetic composition since the degree to which the liquid is absorbed by the magnetic composition can be reduced, the magnetic composition can be appropriately retained in the human body.
  • the management system is a management system for managing the administration of a drug substance including a magnetic composition and a detection device, and the detection device is orally administered into the human body and contains a magnetic substance.
  • a detection device that detects a magnetic composition, in which magnetic sensors having directional anisotropy are arranged in at least three different directions, and at least a magnetic field vector formed by the magnetic material contained in the magnetic composition is measured.
  • an acquisition means for acquiring the time change of the magnetic field vector measured by the three-dimensional magnetic sensor, and a time change of the magnetic field vector acquired by the acquisition means. It comprises a detecting means for detecting the magnetic composition, and the magnetic composition is orally administered into a human body, contains at least the magnetic substance, and is detected by a detection device.
  • the magnetic composition by administering the magnetic composition together with an oral administration composition such as other foods or pharmaceuticals, it can be confirmed that the oral administration composition has been administered into the human body. Further, the magnetic composition can be embedded in the oral administration composition, and it can be confirmed that the oral administration composition has been administered into the human body.
  • the oral administration composition is a nucleated tablet having the magnetic composition as a nucleus or a multilayer tablet in which a substance other than the magnetic substance is laminated on the magnetic substance, and at least one layer thereof is the magnetic composition. It may be a multi-layered tablet.
  • the substance other than the magnetic substance may contain at least one or more components of a drug substance, an enteric substance, a poorly water-soluble substance, an oil and fat, and a lubricant.
  • the oral administration composition may be a capsule filled with a powder, fine granules, granules or small tablets containing a medicine together with the magnetic composition.
  • the oral administration composition may be in a form in which the magnetic composition contains an active ingredient such as a medicine or a specified health food.
  • the medication management system can control that the oral administration composition has been administered to the human body by using the apparatus of the first aspect of the present invention and the magnetic composition of the second aspect. ..
  • FIG. It is a table which shows the composition of each sample in Example 2. It is a table which shows the measurement result of the weight loss rate in Example 2. It is a graph which shows the measurement result of the weight loss rate in Example 3. It is a table which shows the charge amount in Example 4. It is a table which shows the charge amount in Example 5. It is a table which shows the charge amount in Example 8. It is a graph which shows the measurement result of the magnetic flux density in Example 8. It is a graph which shows the measurement result of the magnetic flux density in Example 9. It is a graph which shows the measurement result of the magnetic flux density in Example 9. It is a graph which shows the measurement result of the magnetic flux density in Example 10. It is a graph which shows the measurement result of the magnetic flux density in Example 10.
  • the detection device 1 is a device for detecting the magnetic composition 9 administered by mouth into the human body.
  • the magnetic composition 9 has at least a magnetic material. Details of the magnetic composition 9 will be described later.
  • the detection device 1 measures the magnetic field vector formed by the magnetic material of the magnetic composition 9 orally administered into the body from outside the human body with a three-dimensional magnetic sensor 5, and detects that the magnetic composition 9 is inside the human body. To do.
  • the detection device 1 includes a control circuit unit 2, a power supply unit 31, a display unit 32, sensor heads 6A and 6B (collectively referred to as “sensor head 6”), and an acceleration sensor 7.
  • the sensor head 6 is attached to the wear W worn on the human body by a hook-and-loop fastener or the like.
  • the sensor head 6 is arranged in the vicinity of the anterior side of the stomach in the front surface of the human body.
  • the sensor heads 6A and 6B are arranged in the left-right direction.
  • the sensor head 6A is arranged on the left side (right side when viewed from the human body) with respect to the center in the left-right direction of the human body.
  • the sensor head 6B is arranged on the left side (left side when viewed from the human body) with respect to the center in the left-right direction of the human body.
  • Three-dimensional magnetic sensors 51 and 52 are incorporated in the sensor head 6A.
  • the three-dimensional magnetic sensors 51 and 52 are arranged in the vertical direction.
  • the three-dimensional magnetic sensor 51 is arranged above the three-dimensional magnetic sensor 52.
  • Three-dimensional magnetic sensors 53 and 54 are incorporated in the sensor head 6B.
  • the three-dimensional magnetic sensors 53 and 54 are arranged in the vertical direction.
  • the three-dimensional magnetic sensor 53 is arranged above the three-dimensional magnetic sensor 54. That is, the three-dimensional magnetic sensors 51 to 54 are attached to different positions on the human body.
  • the three-dimensional magnetic sensors 51 to 54 are collectively referred to as "three-dimensional magnetic sensor 5".
  • the three-dimensional magnetic sensor 5 arranges three magnetic impedance sensors (MI sensors) having directional anisotropy in three axial directions (X-axis direction, Y-axis direction, Z-axis direction) orthogonal to each other.
  • the X-axis direction, the Y-axis direction, and the Z-axis direction correspond to, for example, the left-right direction, the front-back direction, and the up-down direction, respectively.
  • Each MI sensor can measure the strength of a specific directional component (X-axis component, Y-axis component, Z-axis component) in the magnetic field vector formed by the magnetic material contained in the magnetic composition 9.
  • Having directional anisotropy means that each MI sensor can measure only the strength of a specific directional component of the magnetic field vector.
  • the three MI sensors are an X-axis sensor capable of measuring the X-axis component of the magnetic field vector, a Y-axis sensor capable of measuring the Y-axis component of the magnetic field vector, and a Z-axis component of the magnetic field vector. Includes possible Z-axis sensors.
  • the three-dimensional magnetic sensor 5 is connected to the control circuit unit 2 described later via the cable C1.
  • the three-dimensional magnetic sensor 5 outputs a signal indicating a magnetic field vector measured by each of the X-axis sensor, the Y-axis sensor, and the Z-axis sensor to the control circuit unit 2.
  • the detection range 50A When the magnetic field vector formed by the magnetic material of the magnetic composition 9 is measured by the three-dimensional magnetic sensor 5, the range in which the magnetic field vector having a predetermined size or larger can be detected is referred to as a detection range 50A.
  • the detection range 50A corresponding to each of the three-dimensional magnetic sensors 51, 52, 53, 54 is shown by the detection ranges 51A, 52A, 53A, 54A.
  • the control circuit unit 2 is arranged at a position away from the human body.
  • the control circuit unit 2 acquires the signal output from the three-dimensional magnetic sensor 5 via the cable C1.
  • the control circuit unit 2 determines whether or not the magnetic composition 9 is detected in the human body based on the magnetic field vector indicated by the acquired signal.
  • the power supply unit 31 is connected to the control circuit unit 2 via the cable C2 to supply the drive power supply for the control circuit unit 2.
  • the display unit 32 is connected to the control circuit unit 2 via the cable C3.
  • the display unit 32 has an LCD, and displays characters and symbols on the LCD in response to an instruction from the control circuit unit 2.
  • the control circuit unit 2, the power supply unit 31, and the display unit 32 may be directly attached to the human body together with the sensor head 6.
  • the power supply unit 31 and the display unit 32 may be integrated with the control circuit unit 2.
  • the acceleration sensor 7 is attached to the wear W worn on the human body by a hook-and-loop fastener or the like.
  • the acceleration sensor 7 is connected to the control circuit unit 2 via the cable C4.
  • the acceleration sensor 7 measures an acceleration of a magnitude corresponding to the movement of the wear W linked to the human body.
  • the acceleration sensor 7 outputs a signal indicating the magnitude of the measured acceleration to the control circuit unit 2.
  • the control circuit unit 2 acquires the signal output from the acceleration sensor 7 via the cable C4.
  • the control circuit unit 2 determines the state of the position fluctuation of the human body wearing the wear W based on the magnitude of the acceleration indicated by the acquired signal.
  • the control circuit unit 2 includes a CPU 21, a storage unit 22, and an interface (I / F) circuit 23.
  • the CPU 21 controls the operation of the detection device 1 in an integrated manner.
  • the storage unit 22 stores programs, setting parameters, and the like executed by the CPU 21.
  • the I / F circuit 23 is an interface element for connecting to an external device via cables C1 to C4.
  • the CPU 21, the storage unit 22, and the I / F circuit 23 are electrically connected to each other.
  • the three-dimensional magnetic sensor 5 is electrically connected to the CPU 21 via the cable C1 and the I / F circuit 23.
  • the power supply unit 31 is connected to the control circuit unit 2 via the cable C2, and supplies drive power to the CPU 21, the storage unit 22, and the I / F circuit 23.
  • the display unit 32 is electrically connected to the CPU 21 via the cable C2 and the I / F circuit 23.
  • the acceleration sensor 7 is electrically connected to the CPU 21 via the cable C4 and the I / F circuit 23.
  • Each component of the magnetic field vector measured by the three-dimensional magnetic sensor 5 in the X-axis direction, the Y-axis direction, and the Z-axis direction is referred to as Bx, By, and Bz.
  • Bx, By, and Bz correspond to a magnetic field vector measured by the X-axis sensor of the three-dimensional magnetic sensor 5, a magnetic field vector measured by the Y-axis sensor, and a magnetic field vector measured by the Z-axis sensor, respectively.
  • the magnetic field vector measured by the three-dimensional magnetic sensor 5 is referred to as B or B (Bx, By, Bz).
  • the unit of magnitude of the magnetic field vectors B, Bx, By, and Bz is nT.
  • Equation (1) is actually calculated by the following equation (2).
  • Equation (2) shows the calculation formula of dBx / dt
  • the calculation formulas of dBy / dt and dBz / dt are also the same.
  • ⁇ t indicates the sampling period (for example, 0.1005 s) of the signal output from the three-dimensional magnetic sensor 5.
  • Bx (t) is a magnetic field vector measured by the three-dimensional magnetic sensor 5 after a lapse of time t (s) from the start of measurement.
  • the time change ⁇ ' which is the time derivative of the angle ⁇ (rad) of the magnetic field vector B, satisfies the relationship of the following equation (3).
  • indicates the magnitude of the magnetic field vector B.
  • indicates the magnitude of the time change B'of the magnetic field vector B.
  • per unit amount is defined.
  • the value R' corresponds to the value obtained by dividing the time change ⁇ 'by
  • the magnetic composition 9 orally administered into the human body when the magnetic composition 9 orally administered into the human body is present in the stomach, the magnetic composition 9 also moves according to the peristaltic movement of the stomach. At this time, the direction of the magnetic field vector formed by the magnetic material fluctuates with the period of peristaltic motion. Therefore, in the CPU 21 of the control circuit unit 2, R'is -0.02 rad or less or 0.02 rad or more (R' ⁇ -0.02 rad or 0.02 rad ⁇ R'), and
  • ⁇ 0.02 rad that is, ⁇ 1.1 deg
  • other values may be used.
  • the main process executed by the CPU 21 will be described with reference to FIG.
  • the CPU 21 executes the main process in a predetermined sample cycle (for example, 0.1005 s) based on the program stored in the storage unit 22.
  • the CPU 21 acquires the signal output from the acceleration sensor 7 and specifies the magnitude of the acceleration.
  • the CPU 21 compares the magnitude of the specified acceleration with a predetermined threshold value.
  • the CPU 21 determines that the position fluctuation of the human body to which the acceleration sensor 7 is attached is large via the wear W (S11: NO). In this case, the CPU 21 ends the main process.
  • the CPU 21 determines that the position fluctuation of the human body is small (S11: YES). In this case, the CPU 21 advances the process to S13.
  • the CPU 21 acquires the signals output by the three-dimensional magnetic sensors 51 to 54, and specifies the magnetic field vectors B (Bx, By, Bz) measured by each of the three-dimensional magnetic sensors 51 to 54 for each of the three-dimensional magnetic sensors 51 to 54 (S13).
  • the CPU 21 calculates the time change ⁇ 'of the specified magnetic field vector B for each of the three-dimensional magnetic sensors 51 to 54 based on the equations (1) to (3) (S15). Further, the CPU 21 calculates the value R'for each of the three-dimensional magnetic sensors 51 to 54 based on the equation (4) (S17).
  • the CPU 21 executes the following processing for each of the three-dimensional magnetic sensors 51 to 54.
  • the CPU 21 determines whether
  • the above 50 nT is an example of the threshold value, and may be another value.
  • the CPU 21 determines whether the processes of S19, S21, S23, and S25 have been executed for all of the three-dimensional magnetic sensors 51 to 54 (S27). When the CPU 21 determines that the processing has not been executed for all of the three-dimensional magnetic sensors 51 to 54 (S27: NO), the processing is returned to S19. The CPU 21 repeats the processing of S19, S21, S23, and S25 while changing the target three-dimensional magnetic sensor 5 until all of the three-dimensional magnetic sensors 51 to 54 are processed. When the CPU 21 determines that the processing has been executed for all of the three-dimensional magnetic sensors 51 to 54 (S27: YES), the processing proceeds to S29.
  • the CPU 21 displays a notification image on the display unit 32 indicating whether or not the magnetic composition 9 is present at the positions of the detection ranges 51A to 54A for each of the three-dimensional magnetic sensors 51 to 54 (S29). The CPU 21 ends the main process.
  • Example 1 The results of the experiment conducted using the detection device 1 will be described.
  • the sensor heads 6A and 6B shown in FIG. 1 were used. Experiments were performed for 10 minutes each with and without oral administration of the magnetic composition 9.
  • the detection device 1 acquired the signal output from the three-dimensional magnetic sensor 5 with a sample period (0.1005 s). Then, whether or not the magnetic composition 9 is within the detection range 50A of each of the three-dimensional magnetic sensors 51 to 54 in the human body was determined 6000 times in total for each sampling cycle.
  • FIG. 3 shows the number of times that the magnetic composition 9 was determined to be within the detection range 50A by each of the three-dimensional magnetic sensors 51 to 54.
  • the number of times that the magnetic composition 9 was determined to be present in the human body before the administration of the magnetic composition 9 was within the range of 0 to 2 times for each of the three-dimensional magnetic sensors 51 to 54.
  • the number of times the magnetic composition 9 was determined to be present in the human body after the administration of the magnetic composition 9 was 10 times or more, which was significantly higher than that before the administration. Increased.
  • the detection device 1 can determine whether or not the magnetic composition 9 is present in the human body.
  • the detection device 1 can specify the site where the magnetic composition 9 is located in the human body in detail by using a plurality of three-dimensional magnetic sensors 5.
  • the magnetic composition 9 is orally administered into the human body and detected by the detection device 1.
  • the magnetic composition 9 may be composed of only a magnetic material, or may contain a component other than the magnetic material. That is, the magnetic composition 9 may contain at least one or more components (hereinafter, referred to as “drug substance or the like”) of a drug substance, an enteric substance, a poorly water-soluble substance, an oil and fat, a lubricant and the like.
  • the magnetic composition 9 can also be in a form that is easy to administer orally. For example, when the magnetic composition 9 is composed of a plurality of components, these components can be mixed and compression molded to obtain a solid tablet.
  • the type of shape of the magnetic composition 9 may be a nucleated tablet, a multi-layer tablet, or the like, in addition to a compression-molded tablet.
  • a nucleated tablet has a nucleus containing at least a magnetic substance, and is formed by adhering a drug substance around the nucleus.
  • the multi-layer tablet is formed by laminating a drug substance or the like on a nucleus containing at least a magnetic substance.
  • the drug substance is a medical drug for diagnosing, treating, and preventing diseases of the human body by being orally administered.
  • the drug substance is prepared according to the purpose of use.
  • An enteric substance is a substance that does not dissolve in the stomach but has the property of being soluble in the intestine.
  • the residence time of the orally administered magnetic composition 9 in the stomach can be adjusted according to the type and content of the enteric substance contained in the magnetic composition 9.
  • a tamarind polymer is used as the enteric substance.
  • a poorly water-soluble substance is a substance having a property of being insoluble in the intestine.
  • ethyl cellulose is included as a poorly water-soluble substance.
  • the fats and oils repel the water adhering to the magnetic composition 9 in the human body, and suppress the disintegration of the magnetic composition 9 as the water permeates the inside of the magnetic composition 9.
  • hydrogenated oil is used as the fat and oil.
  • the lubricant suppresses the adhesion of the raw material of the magnetic composition 9 to the molding apparatus when the magnetic composition 9 is molded as a tablet.
  • magnesium stearate is used as the lubricant.
  • the magnetic material is a magnetic substance and contains at least iron oxide. In the present embodiment, the magnetic material contains at least one of maghemite, magnetite, and epsilon iron oxide as iron oxide.
  • the magnetic composition 9 is adjusted for the type and content of each main component (enteric substance, poorly water-soluble substance, fat, oil, lubricant, etc.) so that it stays in the stomach for at least 1 hour.
  • the detection device 1 can secure the time required to detect the magnetic composition 9 that stays in the stomach, so that the magnetic composition 9 can be detected easily and accurately.
  • the magnetic composition 9 may maintain its shape without collapsing until it is excreted from the body.
  • Example 2 The disintegration properties of the magnetic composition 9 in the stomach and intestine were evaluated.
  • Maghemite ⁇ -MRD, manufactured by Titan Kogyo, Ltd.
  • a methacrylic acid copolymer LD (Eudragid L100-55, manufactured by Rehm Co., Ltd.) was used as an enteric substance.
  • Ethyl cellulose (Etocell 10FP, manufactured by Dow Chemical Co., Ltd.) was used as a poorly water-soluble substance.
  • Hydrogenated oil (Labriwax 101, manufactured by Freund Sangyo Co., Ltd.) was used as the fat and oil.
  • Magnesium stearate manufactured by Marincrot was used as the lubricant. These were prescribed so as to be the charged amount (unit: g) shown in Experiments 1 to 13 in FIG. 4, and tablets were prepared. The allocation of the amount to be charged was in accordance with the Box Benken design of experiments.
  • magnesium stearate was weighed and mixed in a mortar. Then, 1 mL of ethanol (manufactured by Kanto Chemical Co., Inc.) was added, and the powder was wet-kneaded in a mortar. The kneaded powder was dried at 60 ° C. overnight by a shelf-type dryer, and then sized using a sieve having an opening of 1 mm. Next, magnesium stearate was added to the sized granules and mixed. The mixed powder was weighed to about 50 mg and was compression molded with a force of 5 kN using a single-shot tableting machine (Tabflex, manufactured by Okada Seiko Co., Ltd.). As a result, a tablet having a diameter of 4.8 mm was obtained. The tablets had a hardness of 20 N or more (see FIG. 5).
  • the dissolution characteristics of the tablets were evaluated as follows using an dissolution tester (NTR-6300, manufactured by Toyama Sangyo). After the weight of the tablet was measured, the tablet was placed in a vessel containing 900 mL of 0.1 mol / L hydrochloric acid simulating gastric juice or pH 6.8 phosphate buffer simulating intestinal juice, and the paddle rotation speed was 50 rpm. The test solution was stirred at a temperature of 37 ° C. for 2 hours. After stirring for 2 hours, the tablets were taken out, dried overnight at 60 ° C. in a shelf dryer, and then the weight of the tablets after the test was measured. The results are shown in FIG.
  • the weight loss rate in 0.1 mol / L hydrochloric acid was about 1% for all tablets, and it was found that the tablets hardly disintegrated in gastric acid.
  • the weight loss rate in the pH 6.8 phosphate buffer solution varies greatly depending on the tablet. From this, it was found that the disintegration property in the intestine can be arbitrarily adjusted by the amount of each material charged.
  • Example 3 The disintegration properties of the magnetic composition 9 in the intestine were evaluated.
  • a methacrylic acid copolymer LD (Eudragid L100-55, manufactured by Rehm Co., Ltd.) was used as an enteric substance.
  • Ethyl cellulose (Etocell 10FP, manufactured by Dow Chemical Co., Ltd.) was used as a poorly water-soluble substance. Then, the weight loss rate (%) in the pH 6.8 phosphate buffer solution was estimated by multiple regression analysis.
  • FIG. 6A shows the weight reduction rate of the magnetic composition 9 when 5% of hydrogenated oil is contained as fat and oil and the ratio of the respective charges of the methacrylic acid copolymer LD and ethyl cellulose is adjusted.
  • FIG. 6B shows the weight loss rate of the magnetic composition 9 when fats and oils are not included and the ratio of the respective charges of the methacrylic acid copolymer LD and ethyl cellulose is adjusted.
  • Example 4 The method for preparing the magnetic composition 9 was evaluated.
  • Maghemite as a magnetic substance, methacrylic acid copolymer LD as an enteric substance, ethyl cellulose as a water-insoluble substance, and hydrogenated oil as fats and oils were added to a 100 L super mixer (manufactured by Kawata Co., Ltd.). The same products as in Example 2 were used for each. Mixing was carried out at a blade speed of 460 rpm for 3 minutes. Next, ethanol was added while rotating the blade at 460 rpm, and granulation was carried out for 3 minutes. The granules obtained by granulation were dried overnight at 60 ° C. using a shelf-type dryer.
  • the granules were molded by a rotary locking machine (AQUA3, manufactured by Kikusui Seisakusho) at a turntable rotation speed of 40 rpm and a compression pressure of 13.5 kN. As a result, a tablet having a diameter of 6 mm and a weight of 140 mg was obtained.
  • Example 5 A method of molding the magnetic composition 9 as a nucleated tablet was evaluated.
  • Spray-dried lactose (Super Tab 11SD, manufactured by DMV), low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Co., Ltd.), magnesium stearate (manufactured by Marin Clot) are mixed in a plastic bag to support chemical substances.
  • the outer layer powder to be used was prepared. The amount of each material charged is shown in FIG.
  • this outer layer powder and the tablet obtained in Example 4 it was molded by a rotary tableting machine (AQUA-LD, manufactured by Kikusui Seisakusho) at a turntable rotation speed of 15 rpm and a compression pressure of 22 kN. As a result, a nucleated tablet in which a drug substance or the like was attached around the nucleus containing at least a magnetic substance was obtained.
  • the weight of the outer layer powder was 270 mg.
  • the nucleated tablet had a diameter of 9 mm and a weight of 410 mg.
  • Example 6 The method of molding the magnetic composition 9 as a multilayer lock was evaluated.
  • the granules (weight 140 mg) used in the process of obtaining tablets in Example 4 and the outer layer powder (weight 270 mg) prepared in Example 5 were used, and a rotary tableting machine (AQUA-LD, Kikusui) was used. It was molded by a turntable rotation speed of 15 rpm and a compression pressure of 8 kN.
  • a multi-layer lock in which a drug substance or the like was laminated on the surface of a nucleus containing at least a magnetic substance was obtained.
  • the multi-layer tablet had a diameter of 9 mm and a weight of 410 mg.
  • Example 7 The method for preparing the magnetic composition 9 is evaluated.
  • Maghemite as a magnetic substance, methacrylic acid copolymer LD as an enteric substance, ethyl cellulose as a water-insoluble substance, hydrogenated oil as an oil and fat, and a chemical substance are charged into a 100 L super mixer (manufactured by Kawata Co., Ltd.). The same products as in Example 2 are used for each. Mixing is performed for 3 minutes at a blade speed of 460 rpm. Next, ethanol is added while rotating the blade at 460 rpm, and granulation is carried out for 3 minutes. The granules obtained by granulation are dried overnight at 60 ° C. using a shelf-type dryer.
  • crushing and sizing is performed by a power mill (manufactured by Dalton) at a screen mesh size of 1.0 mm and a blade rotation speed of 2000 rpm.
  • Magnesium stearate is added to the granules as a lubricant and mixed in a plastic bag.
  • Granules are molded by a rotary locker (AQUA3, manufactured by Kikusui Seisakusho) at a turntable rotation speed of 40 rpm and a compression pressure of 13.5 kN. This gives a tablet with a diameter of 6 mm and a weight of 140 mg.
  • Example 8 The detectability of the magnetic composition 9 by the detection device 1 was evaluated.
  • the tablet having a slow dissolution rate the tablet obtained in Example 4 (referred to as the first tablet) was used. Tablets with a high dissolution rate were molded by the following method. Spray-dried lactose (Super Tab 11SD, manufactured by DMV), low-degree-of-substitution hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical), and magnesium stearate (manufactured by Marin Clot) were weighed in the amounts shown in FIG. Mixed in a mortar.
  • An MI sensor was attached to an dissolution tester (NTR-6300, manufactured by Toyama Sangyo) in order to simulate the magnetic signal from the stomach of the human body when the sample tablet was orally administered. Then, the magnetic flux density of the magnetic signal detected when the sample tablet was put into 0.1 mol / L hydrochloric acid (referred to as elution test solution) and stirred was measured by the MI sensor. The distance from the tablet to the MI sensor was about 15 cm. The stirring was performed using a rotating basket at a rotation speed of 200 rpm.
  • the graph of FIG. 10A shows the magnetic flux density of the magnetic signal detected in the absence of the sample tablet.
  • the graph of FIG. 10B shows the magnetic flux density immediately after the second tablet is put into the dissolution test solution.
  • the graph of FIG. 10C shows the magnetic flux density immediately after the first tablet is put into the dissolution test solution.
  • the graph of FIG. 10D shows the magnetic flux density 1 hour after the first tablet was put into the dissolution test solution.
  • the graph of FIG. 10 (E) shows the magnetic flux density 2 hours after the first tablet was put into the dissolution test solution.
  • the graph of FIG. 10F shows the magnetic flux density 4 hours after the first tablet was put into the dissolution test solution.
  • Example 9 The detectability of the magnetic composition 9 was evaluated.
  • Three-dimensional magnetic sensors 5 (X-axis sensor, Y-axis sensor, Z-axis sensor) were attached to two places, the anterior abdomen and the flank of the human body. Magnetic signals are detected by each of the X-axis sensor, Y-axis sensor, and Z-axis sensor before and after the tablets obtained in Example 2 are orally administered, and the magnetic flux density is measured. Was done. A bandpass filter was applied to the measurement results, and the frequency component (0.05 Hz ⁇ 0.03 Hz) of the peristaltic movement of the stomach was extracted.
  • FIG. 11 shows the measurement results of the X-axis sensor, the Y-axis sensor, and the Z-axis sensor attached to two places (anterior abdomen and flank) of the human body in a state where the tablet is not orally administered.
  • the horizontal axis represents time (seconds), and the vertical axis represents magnetic flux density (nT).
  • (A) shows the measurement result when 2 hours have passed after lunch.
  • (B) shows the measurement result before dinner.
  • (C) shows the measurement result after dinner.
  • FIG. 12 shows the measurement results of the X-axis sensor, the Y-axis sensor, and the Z-axis sensor attached to two places (anterior abdomen and flank) of the human body in the state after the tablet is orally administered.
  • the horizontal axis represents time (seconds), and the vertical axis represents magnetic flux density (nT).
  • A shows the measurement result immediately after the tablet was administered.
  • B shows the measurement result when 2 hours have passed after the administration of the tablet.
  • C shows the measurement result when 4 hours have passed after the administration of the tablet.
  • Example 10 The relationship between the amount of the magnetic substance added to the magnetic composition 9 and the magnetic flux density was evaluated.
  • the granules used in the process of obtaining tablets in Example 4 were weighed and compression-molded by a single-shot tableting machine (Tabflex, manufactured by Okada Seiko Co., Ltd.). As a result, a third tablet having a granule weight of about 26 mg, a fourth tablet having a granule weight of 52 mg, and a fifth tablet having a granule weight of 129 mg were obtained.
  • the third tablet has a diameter of 3.5 mm and contains about 20 mg of maghemite.
  • the third tablet was molded at a compression pressure of 3 kN.
  • the fourth tablet is 5 mm in diameter and contains about 40 mg of maghemite.
  • the fourth tablet was molded at a compression pressure of 5 kN.
  • the fifth tablet is 6 mm in diameter and contains about 100 mg of maghemite.
  • the fifth tablet was molded at 10 kN.
  • the third to fifth tablets were magnetized with neodymium magnets. The magnetic flux densities at distances of 10 cm, 15 cm, and 20 cm from each tablet were measured using an MI sensor.
  • the measured magnetic flux density increases as the content of maghemite increases. It was also found that the relationship between the maghemite content and the magnetic flux density is substantially linear. Furthermore, it was confirmed that the closer the distance between the tablet and the three-dimensional magnetic sensor 5 is, the greater the magnetic flux density measured by the MI sensor.
  • the detection device 1 calculates the time change of the magnetic field vector B measured by the three-dimensional magnetic sensor 5 (S15), and detects the magnetic composition 9 orally administered into the human body based on the calculation result (S21). .. In this case, the detection device 1 can detect the magnetic composition 9 by using one three-dimensional magnetic sensor 5. Therefore, the detection device 1 can reduce the size and cost of the device as compared with the case where a plurality of three-dimensional magnetic sensors must be used to detect the magnetic composition 9.
  • the detection device 1 calculates the time change ⁇ 'of the angle ⁇ of the magnetic field vector B (S15).
  • of the value R' which is obtained by dividing the time change ⁇ 'of the angle ⁇ of the magnetic field vector B by the magnitude of the time change
  • it is larger than 02 (S21: YES)
  • the detection device 1 can detect the magnetic composition 9 when, for example, the angle ⁇ of the magnetic field vector B changes with time in response to the movement of the magnetic composition 9 in the human body.
  • the detection device 1 can appropriately detect that the magnetic composition 9 is in the stomach based on the time change ⁇ 'of the angle ⁇ of the magnetic field vector B.
  • the detection device 1 has three-dimensional magnetic sensors 51 to 54 that are attached to different positions of the human body.
  • the detection device 1 determines that
  • the detection device 1 includes an acceleration sensor 7.
  • the detection device 1 determines whether the position fluctuation of the human body is small based on the output result of the acceleration sensor 7 (S11).
  • the detection device 1 calculates the time change ⁇ 'of the angle ⁇ of the magnetic field vector B to detect the magnetic composition 9.
  • the detection device 1 can acquire the time change ⁇ 'of the angle ⁇ of the magnetic field vector B when the human body is in a calm state, and can detect the magnetic composition 9. Therefore, since the detection device 1 can minimize the influence of the position fluctuation of the human body on the measurement result, the magnetic composition 9 in the human body can be accurately detected.
  • the magnetic composition 9 is enteric or sparingly soluble in water, and stays in the stomach for at least 1 hour after being orally administered.
  • the detection device 1 may intermittently measure the magnetic field vector B by the three-dimensional magnetic sensor 5 during the period in which the magnetic composition 9 is retained in the stomach, so that the processing load on the detection device 1 can be reduced. , The power saving of the detection device 1 becomes possible.
  • the magnetic composition 9 contains iron oxide as a magnetic material. More specifically, the magnetic composition 9 contains at least one of maghemite, magnetite, and epsilon iron oxide as iron oxide. In this case, the detection device 1 can accurately measure the magnetic field vector B by the three-dimensional magnetic sensor 5. Further, the magnetic composition 9 contains an enteric substance. In this case, the magnetic composition 9 can be prepared so that the behavior of the magnetic composition 9 in the stomach is as desired. Further, the magnetic composition 9 contains a poorly water-soluble substance. In this case, the magnetic composition 9 can be prepared so that the behavior of the magnetic composition 9 in the intestine is as desired. Further, the magnetic composition 9 contains fats and oils. In this case, since the degree to which the liquid is absorbed by the magnetic composition 9 can be reduced, the magnetic composition 9 can be made less likely to collapse. Therefore, the magnetic composition 9 can be appropriately retained in the human body.
  • the magnetic composition 9 contains a magnetic substance, but it can also be a nucleated tablet having a magnetic substance as a nucleus and a chemical substance attached to the periphery, or a multilayer tablet in which magnetic substances are laminated. Further, the magnetic composition 9 and other components such as a drug substance can be encapsulated in a capsule for oral administration. In these cases, the magnetic composition 9 can be easily orally administered to the human body as a pharmaceutical composition.
  • the magnetic composition 9 contained in the orally-administered composition (pharmaceutical composition) containing the drug substance is detected by the detection device 1 to obtain the orally-administered composition or the drug substance contained in the orally-administered composition.
  • the detection device 1 detects the oral administration composition for swallowing, passage through the esophagus, and movement in the stomach or intestine. Therefore, the oral administration composition or the drug substance contained in the oral administration composition can be managed by taking the drug.
  • the detection device 1 has three-dimensional magnetic sensors 51 to 54.
  • the number of three-dimensional magnetic sensors 5 included in the detection device 1 is not limited.
  • the detection device 1 may have only one three-dimensional magnetic sensor 5.
  • the detection device 1 may detect the presence of the magnetic composition 9 by directly comparing the time change ⁇ 'of the angle ⁇ of the magnetic field vector B with a predetermined threshold value. Further, the detection device 1 may detect the magnetic composition 9 based on the time change of the magnitude
  • the detection device 1 may filter the measurement results acquired from the three-dimensional magnetic sensor 5 by using a bandpass filter capable of extracting the frequency of the peristaltic movement of the stomach of 0.05 Hz.
  • the detection device 1 may detect the magnetic composition 9 by calculating the time change ⁇ 'of the angle ⁇ of the magnetic field vector B based on the result obtained by filtering.
  • the detection device 1 does not have to include the acceleration sensor 7.
  • the detection device 1 may detect the magnetic composition 9 regardless of the state of the position change of the human body.
  • the residence time of the magnetic composition 9 in the stomach may be less than 1 hour.
  • the magnetic composition 9 includes at least one of an enteric substance and a poorly water-soluble substance, and does not have to include the other.
  • the magnetic composition 9 does not have to have both an enteric substance and a poorly water-soluble substance.
  • the magnetic composition 9 does not have to have fats and oils.
  • the material included in the magnetic composition 9 as an enteric substance, a poorly water-soluble substance, and an oil / fat is not limited to this embodiment, and other materials may be used.
  • the magnetic composition 9 may include a material in which two or more of maghemite, magnetite, and epsilon iron oxide are combined as iron oxide.
  • the iron oxide is not limited to maghemite, magnetite, and epsilon iron oxide, and other materials may be used.
  • the material included as the magnetic material in the magnetic composition 9 is not limited to iron oxide, and may be another magnetic material.
  • the nucleus of the nucleated tablet or the multilayer tablet may be formed only from the magnetic material.
  • the magnetic composition 9 may be molded in a shape other than a nucleated tablet or a multi-layer tablet.
  • the magnetic composition 9 may be molded by encapsulating each material.
  • the CPU 21 that performs the processing of S15 is an example of the "acquisition means” of the present invention.
  • the CPU 21 that performs the processing of S21 is an example of the “detection means” of the present invention.
  • the CPU 21 that performs the process of S11 is an example of the "determination means” of the present invention.
  • Detection device 5 Three-dimensional magnetic sensor 7: Accelerometer 9: Magnetic composition 21: CPU 51, 52, 53, 54: 3D magnetic sensor

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Abstract

La présente invention concerne un dispositif de détection (1) qui détecte une composition magnétique (9) qui est administrée par voie orale dans un corps humain et qui comprend au moins un corps magnétique. Le dispositif de détection (1) est caractérisé en ce qu'il comprend : au moins un capteur magnétique tridimensionnel (5) dans lequel des capteurs magnétiques ayant une anisotropie directionnelle sont agencés dans au moins trois directions différentes, et qui mesure un vecteur de champ magnétique formé par le corps magnétique inclus dans la composition magnétique (9) ; un moyen d'acquisition pour acquérir une variation temporelle du vecteur de champ magnétique mesuré par le capteur magnétique tridimensionnel (5) ; et un moyen de détection pour détecter la composition magnétique (9) dans le corps humain sur la base de la variation temporelle du vecteur de champ magnétique acquis par le moyen d'acquisition.
PCT/JP2019/042954 2019-10-31 2019-10-31 Dispositif de détection, composition magnétique et système de gestion Ceased WO2021084725A1 (fr)

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Publication number Priority date Publication date Assignee Title
TWI798002B (zh) * 2022-02-23 2023-04-01 弘光科技大學 口腔進食能力評估系統

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016528947A (ja) * 2013-06-20 2016-09-23 エボニック レーム ゲゼルシャフト ミット ベシュレンクテル ハフツングＥｖｏｎｉｋ Ｒｏｅｈｍ ＧｍｂＨ 人体における磁性体を検出する個人化された検出システム
WO2016151915A1 (fr) * 2015-03-25 2016-09-29 オリンパス株式会社 Système de détection de position et système de guidage
WO2019098259A1 (fr) * 2017-11-17 2019-05-23 塩野義製薬株式会社 Préparation pharmaceutique présentant d'excellentes propriétés de photostabilité et de libération de médicament

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007127316A2 (fr) 2006-04-25 2007-11-08 Dow Global Technologies Inc. surveillance de conformité de médicament oral à l'aide de capteurs à champ magnétique
JP2009537567A (ja) 2006-05-17 2009-10-29 ボード オブ リージェンツ オブ ザ ネバダ システム オブ ハイアー エジュケーション オン ビハーフ オブ ザ ユニヴァーシティー オブ ネバダ 磁性流体およびその治療上の使用法
JP2014217707A (ja) 2013-05-11 2014-11-20 株式会社 ライフインターフェイス 生体情報計測装置及び生体情報計測システム
WO2018179255A1 (fr) 2017-03-30 2018-10-04 フジデノロ株式会社 Dispositif de détection de corps magnétique, programme pour amener un ordinateur à effectuer une fonction de détection de corps magnétique, et support d'enregistrement lisible par ordinateur pour enregistrer un programme d'enregistrement

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016528947A (ja) * 2013-06-20 2016-09-23 エボニック レーム ゲゼルシャフト ミット ベシュレンクテル ハフツングＥｖｏｎｉｋ Ｒｏｅｈｍ ＧｍｂＨ 人体における磁性体を検出する個人化された検出システム
WO2016151915A1 (fr) * 2015-03-25 2016-09-29 オリンパス株式会社 Système de détection de position et système de guidage
WO2019098259A1 (fr) * 2017-11-17 2019-05-23 塩野義製薬株式会社 Préparation pharmaceutique présentant d'excellentes propriétés de photostabilité et de libération de médicament

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI798002B (zh) * 2022-02-23 2023-04-01 弘光科技大學 口腔進食能力評估系統

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